Skeletal muscle is a mechanically and energetically active organ, supporting vital processes such as respiration and locomotion, and is a major site of glucose and lipid metabolism. Therefore, maintaining proper muscle mass and function is critical. Muscle incurs damage due to a variety of insults such as use, disuse, aging and pathology. While skeletal muscle does not undergo rapid turnover under normal conditions, upon being damaged, it is capable of executing a robust regenerative response through mobilization of its resident progenitor cells, the satellite cells (Moss F P, Leblond C P, Anat Rec 170:421-436 (1970); Schultz E, Gibson M C, Champion T, J Exp Zool 206(3):451-6 (1978); Snow M H, Cell Tissue Res 186(3):535-40 (1978)). The self-renewal and differentiation capacity of the satellite cells have alluded to the archetypic “stemness,” but their fate seems largely committed (Sinanan A C M, Buxton P G, Lewis M P, Bio Cell 98:203-214 (2006); Beauchamp J R et al., J Cell Biol 151:1221-1234 (2000); Starkey J D et al., J Histochem Cytochem 59(1):33-46 (2011)). In an adult, satellite cells comprise less than 5% of total nuclei on a myofiber; nevertheless, based on their proliferation kinetics and capacity, this is sufficient to regenerate an entire muscle (Schmalbruch H, Hellhammer U, Anat Rec 189:169-176 (1977); Kelly A M, Dev Bio 65(1): 1-10 (1978); Gibson M C, Schultz E, Anat Rec 202(3):329-337 (1982); Bischoff R in Myology, Vol 1, eds Engel A G, Franzini-Armstrong C (McGraw-Hill, Inc., New York), (1994); Zammit P S et al., Exp Cell Res 281:39-49 (2002)).
Upon injury, skeletal muscle responds to damage in three distinct but overlapping phases: degeneration, regeneration and finally remodeling (Charge S B P, Rudnicki M A, Physiol Rev 84:209-238 (2004)). Immediately following the injury, inflammatory cells are recruited to the injury site to promote degeneration of the damaged tissue through necrosis and phagocytosis (Tidball J G, Am J Physiol Regul Integr Comp Physio 288:R345-353 (2005); McLennan I S, J Anat 188:17-28 (1996); Pimorady-Esfahani A, Grounds M D, McMenamin P G, Muscle Nerve 20:158-166 (1997); Vierck J et al., Cell Bio Int 24:263-272 (2000); Arnold L et al., J Exp Med 204(5):1057-1069 (2007)). The subsequent regenerative phase is characterized by mobilization of satellite cells, whereby the progenitor cells proliferate, differentiate and fuse to each other or to the existing fibers to regenerate the muscle (Zammit P S in Skeletal muscle repair and regeneration, eds Schiaffino S, Partridge T (Springer, Dordrecht (2008)). Finally, the contractile proteins are reassembled and function is restored during the remodeling phase.